The proposed research focuses on the neuropeptide glucagon-like-peptide-1 (GLP-1) and its role in controlling for food intake and body weight. FDA-approved GLP-1 receptor (GLP-1R) agonists for the treatment of Type II Diabetes Mellitus (T2DM) produce improvements in blood glucose regulation and, in addition, produce meaningful reductions in food intake and body weight in both humans and animal models. Therefore, recent attention has been given to long-acting GLP-1R agonists as a potential treatment for obesity. It is remarkable to note, however, while nausea and/or vomiting are the major adverse events (i.e. side effect) reported in ~20-50% of T2DM patients prescribed GLP-1R agonists there is very little investigation of the mechanisms mediating the nausea/malaise and virtually no understanding of the significance of nausea/malaise in relation to GLP-1R- mediated suppression of food intake. Experiments in this proposal will examine the potential mechanisms and gastrointestinal and central nervous system (CNS) structures mediating the nausea/malaise following GLP-1R activation by examining: [1] the role of GLP-1Rs expressed on vagal afferent and CNS neurons in mediating the nausea/malaise and food intake suppression of GLP-1R agonists; [2] gastrointestinal mechanisms mediating the nausea/malaise response of GLP-1R agonists. The overall research proposed will provide a framework for development of GLP-1R-mediated treatments with reduced incidence of nausea/vomiting that can be used by a greater population of obese individuals. In addition, results may help identify potential targets for combination drug therapy to ameliorate the malaise side effects of current FDA-approved GLP-1R ligands.